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Background: Currently utilized serum tumor markers and fecal immunochemical tests do not have sufficient diagnostic power for colorectal cancer (CRC) due to their low sensitivities. To establish non-invasive urinary protein biomarkers for early CRC diagnosis, we performed stepwise analyses employing urine samples from CRCs and healthy controls (HCs)., Methods: Among 474 urine samples, 363 age- and sex-matched participants (188 HCs, 175 stage 0-III CRCs) were randomly divided into discovery (16 HCs, 16 CRCs), training (110 HCs, 110 CRCs), and validation (62 HCs, 49 CRCs) cohorts., Results: Of the 23 urinary protein candidates comprehensively identified from mass spectrometry in the discovery cohort, urinary levels of dipeptidase 1 (uDPEP1) and Trefoil factor1 (uTFF1) were the two most significant diagnostic biomarkers for CRC in both training and validation cohorts using enzyme-linked immunosorbent assays. A urinary biomarker panel comprising uDPEP1 and uTFF1 significantly distinguished CRCs from HCs, showing area under the curves of 0.825-0.956 for stage 0-III CRC and 0.792-0.852 for stage 0/I CRC. uDPEP1 and uTFF1 also significantly distinguished colorectal adenoma (CRA) patients from HCs, with uDPEP1 and uTFF1 increasing significantly in the order of HCs, CRA patients, and CRC patients. Moreover, expression levels of DPEP1 and TFF1 were also significantly higher in the serum and tumor tissues of CRC, compared to HCs and normal tissues, respectively., Conclusions: This study established a promising and non-invasive urinary protein biomarker panel, which enables the early detection of CRC with high sensitivity., (© 2024. Japanese Society of Gastroenterology.)

Purpose: To determine the methylation level of the miR-124 promoter in non-neoplastic rectal mucosa of patients with pediatric-onset ulcerative colitis (UC) to predict UC-associated colorectal cancer (UC-CRC)., Methods: Between 2005 and 2017, non-neoplastic rectal tissue specimens were collected from 86 patients with UC, including 13 patients with UC-CRC; cancer tissues were obtained from the latter group. The methylation status of the miR-124 promoter was quantified using bisulfite pyrosequencing and compared between pediatric- and adult-onset UC patients., Results: Patients with pediatric-onset UC experienced a significantly shorter disease duration than those with adult-onset UC. The levels of miR-124 promoter methylation in non-neoplastic rectal mucosa were positively correlated with the age at the diagnosis and duration of UC. The rate of increase in miR-124 methylation was accelerated in patients with pediatric-onset UC compared to those with adult-onset UC. Furthermore, the miR-124 methylation levels in non-neoplastic rectal mucosa were significantly higher in patients with UC-CRC than in those with UC alone (P = 0.02). A receiver operating characteristic analysis revealed that miR-124 methylation in non-neoplastic tissue discriminated between patients with pediatric-onset UC with or without CRC., Conclusion: miR-124 methylation in non-neoplastic rectal mucosa may be a useful biomarker for identifying patients with pediatric-onset UC who face the highest risk of developing UC-CRC., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background and Aim: Post-endoscopic submucosal dissection coagulation syndrome (PECS) is a recognized complication of colorectal endoscopic submucosal dissection (ESD); however, there is a lack of interventions for preventing PECS. We therefore conducted a prospective study to evaluate the utility of maXium, a novel electrosurgical unit, for preventing PECS., Methods: This single-center, prospective cohort study prospectively enrolled patients undergoing colorectal ESD. The voltage and power of the electrosurgical units were measured. PECS was defined as a visual analog scale (VAS) ≥ 30 mm, an increase of VAS ≥ 20 mm from baseline, body temperature ≥ 37.5°C, or white blood cell count ≥ 10 000/μL after ESD. PECS was classified into type I (without extra-luminal air) and type II (with peri-luminal air). The primary endpoint was the incidence of PECS. A sample size of 92 patients was required to ensure the upper limit of the 90% CI for the incidence of PECS was less than 15%., Results: At resistances greater than 400 Ω, the maXium unit allowed submucosal dissection with lower power than with the VIO300D unit. Ninety-one patients meeting the inclusion criteria were included in the final study analysis. The incidence of PECS was 16% (90% CI, 10-23%), comprising type I (11%) and type II (5%) PECS. Simple extra-luminal air without PECS was observed in 7% of patients., Conclusion: Use of the maXium electrosurgical unit did not reduce the incidence of PECS after colorectal ESD; however, the maXium unit had equivalent performance to a conventional electrosurgical unit used for colorectal ESD., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Reovirus, a naturally occurring oncolytic virus, initiates the lysis of tumor cells while simultaneously releasing tumor antigens or proapoptotic cytokines in the tumor microenvironment to augment anticancer immunity. However, reovirus has developed a strategy to evade antiviral immunity via its inhibitory effect on interferon production, which negatively affects the induction of antitumor immune responses. The mammalian adaptor protein Stimulator of Interferon Genes (STING) was identified as a key regulator that orchestrates immune responses by sensing cytosolic DNA derived from pathogens or tumors, resulting in the production of type I interferon. Recent studies reported the role of STING in innate immune responses to RNA viruses leading to the restriction of RNA virus replication. In the current study, we found that reovirus had a reciprocal reaction with a STING agonist regarding type I interferon responses in vitro; however, we found that the combination of reovirus and STING agonist enhanced anti-tumor immunity by enhancing cytotoxic T cell trafficking into tumors, leading to significant tumor regression and survival benefit in a syngeneic colorectal cancer model. Our data indicate the combination of reovirus and a STING agonist to enhance inflammation in the tumor microenvironment might be a strategy to improve oncolytic reovirus immunotherapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC., Patients and Methods: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30., Results: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036)., Conclusions: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Self-expanding metallic stent (SEMS) and trans-anal colorectal tube (TCT) are alternative treatments to conventional emergency surgery for non-right-sided obstructive colon cancer (NROCC). However, the one with better short- and long-term outcomes remains controversial. Thus, this multicenter case-control study aimed to analyze and compare SEMS and TCT for NROCC., Methods: Patients with stage II/III NROCC who underwent surgery between January 2010 and December 2019 at either of the eight selected Japanese affiliate hospitals were, retrospectively, reviewed. Baseline characteristics between the SEMS and TCT groups were adjusted by propensity score (PS) matching., Results: Among 239 reviewed patients (SEMS: 76, TCT: 163), 180 were finally included in two well-balanced cohorts through PS: SEMS group (65 patients) and TCT group (115 patients). Technical success, clinical success, morbidity, and short-term mortality were not significantly different between the two groups. SEMS placement achieved significantly higher rates for primary resection/anastomosis without stoma (SEMS: 90.8% vs. TCT: 77.4%, p < 0.001) and laparoscopic surgery (SEMS: 64.6% vs. TCT: 43.5%, p < 0.001) than TCT placement. However, 5-year overall survival (SEMS: 83.7% vs. TCT: 86.4%; p = 0.822) and 5-year relapse-free survival (SEMS: 64.7% vs. TCT: 66.4%; p = 0.854) showed no significant differences between these groups., Conclusions: Both SEMS and TCT revealed similar long-term outcomes, but SEMS placement was better in achieving primary resection/anastomosis and laparoscopic surgery in patients with stage II/III NROCC., (© 2023. Japanese Society of Gastroenterology.)

Purpose: Endoscopic clipping closure after colorectal endoscopic submucosal dissection (ESD) did not reduce the incidence of post-ESD coagulation syndrome (PECS) in our recent randomized controlled trial (RCT); however, the definition of PECS is still controversial. The aim of this study is to establish optimal definition of PECS with additional analysis of RCT based on another definition., Methods: In this multicenter, single-blind RCT, individuals were randomly assigned to colorectal ESD followed by endoscopic clipping closure or non-closure. In this post hoc analysis, the definition of PECS was modified as both localized abdominal pain on visual analogue scale and inflammatory response (fever or leukocytosis), from either localized abdominal pain or inflammatory response in the original study. All participants underwent a computed tomography after ESD, and PECS was classified into type I, conventional PECS without extra-luminal air, and type II, PECS with peri-luminal air., Results: A total of 155 patients (84 in the non-closure group and 71 in the closure group) were analyzed. As a result of criteria modification, 21 type I PECS and four type II PECS cases in the original study, which included patients with clear pain and inflammatory response, were downgraded to no adverse event and simple peri-luminal air, respectively. The frequency of PECS showed no significant difference between non-closure and closure groups., Conclusion: Clipping closure after colorectal ESD does not reduce the incidence of PECS regardless of the diagnostic criteria. Either localized abdominal pain or inflammatory response might be optimal criteria of PECS (UMIN000027031)., Trial Registration Number: UMIN000027031 DATE OF REGISTRATION: April 18, 2017.

The high degree of morbidity and mortality in colorectal cancer (CRC) patients is largely due to the development of chemoresistance against conventional chemotherapeutic drugs. In view of the accumulating evidence that various dietary botanicals offer a safe, inexpensive and multi-targeted treatment option, herein, we hypothesized that a combination of Andrographis paniculata and Oligomeric Proanthocyanidins (OPCs) might interact together with regard to anti-tumorigenic activity in CRC. As a result, we demonstrated the enhanced anti-cancer activity between these two botanical extracts in terms of their ability to inhibit cancer cell growth, suppress colony formation and induce apoptosis. Furthermore, we validated these findings in subcutaneous xenograft model and in patient derived primary epithelial 3D organoids. Transcriptomic profiling identified involvement of metabolic pathways and ferroptosis-associated genes, including HMOX1, GCLC and GCLM, that may be responsible for the increased anti-tumorigenic activity by the two compounds. Collectively, our study provides novel evidence in support of the combinatorial use of andrographis and OPCs as a potential therapeutic option, perhaps as an adjunctive treatment to classical drugs, in patients with colorectal cancer.

Background: Programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) play a pivotal role in cancer immunotherapy. Each of these molecules has a membrane-bound receptor form (mPD-L1/mCTLA-4) and a soluble form (sPD-L1/sCTLA-4). However, these prognostic impacts in colorectal cancer (CRC) remain unclear., Methods: We immunohistochemically scored tumoral mPD-L1/mCTLA-4 expression and quantified preoperative circulating sPD-L1/sCTLA-4 levels using matched serum specimens from 131 patients with pStage I-III CRC. We also examined the association between these statuses and tumor infiltrating lymphocytes (TILs) in these patients., Results: Elevated levels of mPD-L1, mCTLA-4, sPD-L1 and sCTLA-4 were significantly correlated with poor overall survival (OS) and disease-free survival (DFS). Co-high expression of tumoral mPD-L1 and mCTLA-4 or co-elevated levels of serum sPD-L1 and sCTLA-4 were strongly correlated with poor OS and DFS. Multivariate analysis revealed that both statuses were negative independent prognostic factors for OS [hazard ratio (HR) 3.86, 95% confidence interval (95% CI) 1.71-8.51, p = 0.001; HR 5.72, 95% CI 1.87-14.54, p = 0.004, respectively] and DFS (HR 2.53, 95% CI 1.23-4.95, p = 0.01; HR 6.88, 95% CI 2.42-17.13, p = 0.0008, respectively). Although low expression of tumoral mCTLA-4 was significantly correlated with increased CD8(+) TILs, there was no correlation in any other combination., Conclusions: We verified the prognostic impacts of mPD-L1, mCTLA-4, sPD-L1 and sCTLA-4 in pStage I-III CRC patients. Dual evaluation of immune checkpoint molecules in primary tissues or preoperative serum could identify a patient population with poor prognosis in these patients.

Background & Aims: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic., Methods: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients., Results: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients., Conclusions: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality in the USA. As much as 50-60% of CRC patients develop resistance to 5-fluorouracil (5FU)-based chemotherapeutic regimens, attributing the increased overall morbidity and mortality. In view of the growing evidence that active principles in various naturally occurring botanicals can facilitate chemosensitization in cancer cells, herein, we undertook a comprehensive effort in interrogating the activity of one such botanical-andrographis-by analyzing its activity in CRC cell lines [both sensitive and 5FU resistant (5FUR)], a xenograft animal model and patient-derived tumor organoids. We observed that combined treatment with andrographis was synergistic and resulted in a significant and dose-dependent increase in the efficacy of 5FU in HCT116 and SW480 5FUR cells (P < 0.05), reduced clonogenic formation (P < 0.01) and increased rates of caspase-9-mediated apoptosis (P < 0.05). The genomewide expression analysis in cell lines led us to uncover that activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways were the key mediators for the anti-cancer and chemosensitizing effects of andrographis. Subsequently, we validated our findings in a xenograft animal model, as well as two independent CRC patient-derived organoids-which confirmed that combined treatment with andrographis was significantly more effective than 5FU and andrographis alone and that these effects were in part orchestrated through dysregulated expression of key genes (including HMOX1, GCLC, GCLM and TCF7L2) within the ferroptosis and Wnt-signaling pathways. Collectively, our data highlight that andrographis might offer a safe and inexpensive adjunctive therapeutic option in the management of CRC patients., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Colorectal cancer (CRC) with acute colorectal obstruction (ACO) is an emergency. Transanal colorectal tube (TCT) use can be a safe single-stage surgery with laparoscopy-assisted colectomy; it offers long-term outcomes equivalent to emergency surgery for stage-II/III CRC with ACO. Self-expanding metallic stent use, another alternative, may have detrimental pathological and molecular effects, whereas the pathological impact of TCT placement remains unclear. We hypothesized that TCT placement might exert little damage on primary tumor. Hence, the current study analyzed the pathological impact of TCT placement for CRC with ACO compared to emergency surgery., Methods: Data from consecutive patients with stage-II/III distal CRC with ACO who underwent surgery between January 2007 and December 2015 were retrospectively reviewed at two Japanese affiliate hospitals. Inflammatory and malignant potential-related parameters were analyzed by a single blinded pathologist. We extracted mRNA from tumor tissues to analyze inflammatory cytokines., Results: Sixty-eight patients with stage-II/III distal CRC with ACO were identified (surgery: 25 patients; TCT: 43 patients). Baseline characteristics were well balanced between the two groups. TCT showed a significantly lower frequency of abscess (surgery vs TCT, 36.0% vs 11.6%; P = 0.017) and a lower tendency of pathological perforation (surgery vs TCT, 20.0% vs 4.7%, respectively; P = 0.091), compared to the surgery group. There were no significant intergroup differences in oncological factors, including perineural invasion (surgery vs TCT, 52.0% vs 62.8%; P = 0.383), microlymphatic involvement (surgery vs TCT, 52.0% vs 58.1%; P = 0.623), and microvascular involvement (surgery vs TCT, 32.0% vs 25.6%; P = 0.570). No significant intergroup differences were found in interleukin (IL)-6, IL-8, or IL-1β gene expression levels (P = 0.580, 0.250, 0.941)., Conclusions: TCT placement had no pathologically detrimental effects on the tumor or surrounding tissues and might be an attractive non-invasive strategy for cases of curative distal CRC with ACO.

Accumulating evidence suggests that aspirin has anti-tumorigenic properties in colorectal cancer (CRC). Herein, we undertook a comprehensive and systematic series of in vivo animal experiments followed by 3D-mathematical modeling to determine the kinetics of aspirin's anti-cancer effects on CRC growth. In this study, CRC xenografts were generated using four CRC cell lines with and without PIK3CA mutations and microsatellite instability, and the animals were administered with various aspirin doses (0, 15, 50, and 100 mg/kg) for 2 weeks. Cell proliferation, apoptosis and protein expression were evaluated, followed by 3D-mathematical modeling analysis to estimate cellular division and death rates and their impact on aspirin-mediated changes on tumor growth. We observed that aspirin resulted in a dose-dependent decrease in the cell division rate, and a concomitant increase in the cell death rates in xenografts from all cell lines. Aspirin significantly inhibited cell proliferation as measured by Ki67 staining (P < 0.05-0.01). The negative effect of aspirin on the rate of tumor cell proliferation was more significant in xenograft tumors derived from PIK3CA mutant versus wild-type cells. A computational model of 3D-tumor growth suggests that the growth inhibitory effect of aspirin on the tumor growth kinetics is due to a reduction of tumor colony formation, and that this effect is sufficiently strong to be an important contributor to the reduction of CRC incidence in aspirin-treated patients. In conclusion, we provide a detailed kinetics of aspirin-mediated inhibition of tumor cell proliferation, which support the epidemiological data for the observed protective effect of aspirin in CRC patients., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Aims: Post endoscopic submucosal dissection coagulation syndrome (PECS) occasionally occurs after colorectal endoscopic submucosal dissection (ESD), presenting with localized abdominal pain and inflammation. We conducted a randomized controlled trial (RCT) to assess the usefulness of endoscopic clipping closure to prevent PECS and delayed perforation (DP)., Methods: This is a multicenter, single-blind RCT. Prospectively enrolled patients undergoing colorectal ESD were randomly allocated to endoscopic clipping closure and nonclosure after ESD, stratifying by institution and tumor size. All participants underwent a computed tomography scan after ESD. PECS was defined as visual analog scale (VAS) ≥30 mm, an increase in VAS ≥20 mm from baseline, body temperature ≥37.5°C or white blood cells ≥10,000/μL after colorectal ESD. DP was defined as PECS accompanied by extraluminal air. The preplanned sample size was 320 patients, and the primary endpoint was the rate of PECS/DP., Results: At the planned interim analysis, this trial was terminated by recommendation of the independent data and safety monitoring committee because conditional power with superiority was lower than the preplanned futility limit. Finally, 155 patients were analyzed. The rate of PECS/DP was 16% (95% confidence interval [CI], 8%-23%) in the nonclosure group and 24% (95% CI, 14%-34%) in the closure group (P = .184). All cases of DP were within minor criteria, and all PECS/DP patients were managed conservatively without surgical treatment. Simple periluminal air without PECS was observed in 16% (95% CI, 8%-23%) in the nonclosure group and 10% (95% CI, 3%-17%) in the closure group., Conclusion: Endoscopic clipping closure could not reduce the high incidence of PECS/DP after colorectal ESD. (University Hospital Medical Network Clinical Trials Registry number: UMIN000027031.)., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Fecal occult blood test (FOBT) and flexible sigmoidoscopy are the currently using screening methods for colorectal cancer (CRC). However, these methods still have problems of high false positive rates in FOBT and increased invasiveness and cost associated with endoscopy. The development of non-invasive biomarkers is thus important for the diagnosis of CRC. Urine is one of the most commonly used samples for mass screening owing to its non-invasive and simple process of collection; however, the discovery of urinary diagnostic biomarkers for malignancies is still challenging and developing. Since urine contains abundant substances reflecting systemic body condition, urinary biomarker might contribute to detect CRC in a completely non-invasive manner. In this review, we describe the current utility of urinary diagnostic biomarkers for CRC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Since oncological outcomes of transanal colorectal tube (TCT) placement, an endoscopic treatment for colorectal cancer (CRC) with acute colorectal obstruction (ACO), remain unknown, this study analyzed long-term outcomes of TCT placement for stage II/III CRC with ACO., Materials and Methods: Data were retrospectively reviewed from consecutive patients with distal stage II/III CRC who underwent surgery between January 2007 and December 2011 at two Japanese hospitals. One hospital conducted emergency surgery and the other performed TCT placement as the standard treatment for all CRCs with ACO. Propensity score (PS) matching was used to adjust baseline characteristics between two groups., Results: Among 754 patients with distal stage II/III CRC, 680 did not have ACO (non-ACO group) and 74 had ACO (ACO group). The PS matching between both hospitals identified 234 pairs in the non-ACO group and 23 pairs in the ACO group. In the non-ACO group, the surgical quality was equivalent between the two institutions, with no significant differences in overall survival (OS) and disease-free survival (DFS). In the ACO group, the rate of primary resection/anastomosis was higher in the TCT group than in the surgery group (87.0% vs. 26.1%, p < 0.001). No significant differences were noted between the surgery and the TCT groups in OS (5-year OS, 61.9% vs. 51.5%; p=0.490) and DFS (5-year DFS, 45.9% vs. 38.3%; p=0.658)., Conclusion: TCT placement can achieve similar long-term outcomes to emergency surgery, with a high rate of primary resection/anastomosis for distal stage II/III colon cancer with ACO.

Background: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC., Materials and Methods: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG)., Results: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS)., Conclusion: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC., Implications for Practice: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab., (© AlphaMed Press 2018.)

Background: Obstructive colorectal cancer (CRC) is an emergency situation with high morbidity and mortality, but long-term outcomes of stage II/III obstructive CRC remain unclear. The aim of this study was to evaluate prognostic factors, including colorectal obstruction., Methods: Data were retrospectively reviewed from consecutive patients with stage II/III CRC who underwent curative surgery between January 2007 and December 2011 at two Japanese institutions. We analyzed overall survival (OS) and relapse-free survival (RFS), according to various prognostic factors including colorectal obstruction., Results: In total, 979 patients with stage II/III CRC were identified for this study. Among these 979 patients, 94 patients showed colorectal obstruction (9.6%). In both stage II and stage III CRCs, colorectal obstruction showed significantly poorer OS and RFS compared to non-obstruction (5-year OS, obstruction vs. non-obstruction, stage II: 65.9 vs. 86.5%, P = 0.002; stage III: 55.9 vs. 73.6%, P = 0.007) (5-year RFS, obstruction vs. non-obstruction, stage II: 59.2 vs. 77.8%, P = 0.008; stage III 31.3 vs. 56.3%, P = 0.001). Multivariate analysis demonstrated colorectal obstruction as a significant independent and poor prognostic factor in terms of both OS (hazard ratio (HR) 2.469; 95% CI 1.339-4.545; P = 0.004) and RFS (HR 1.992; 95% CI 1.160-3.425; P = 0.012) for stage II CRC, as well as pT4 stage. On multivariate analysis for stage III CRC, colorectal obstruction was a significant predictor of poor RFS (HR 1.626; 95% CI 1.070-2.469; P = 0.023), but not poor OS., Conclusions: Colorectal obstruction is an independent poor prognostic factor for stage II CRC. Adjuvant chemotherapy might be feasible for stage II CRC with colorectal obstruction.

Aims: We aimed to investigate the relationship of colorectal cancer prognosis and inflammatory parameters, including neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR), with reference to circulating myeloid-derived suppressor cells (MDSCs) in the current study., Patients and Methods: Thirty-five patients who underwent curative-intent surgery were enrolled.　A receiver-operating characteristic curve (ROC) was used to assess the usefulness of candidates for prognostic factors. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method, and the candidates for prognostic factors were assessed by a Cox proportional hazard model., Results: ROC curve analyses determined cutoff values for NLR and LMR as 2.9 and 2.4, respectively. The percentage of MDSCs in patients with LMR ≤ 2.4 was statistically higher than in those with LMR > 2.4 (p = 0.012). The patients with LMR ≤ 2.4 exhibited a statistically lower RFS than those with LMR > 2.4 (p = 0.008). These results were also observed in patients with stage II + III disease. LMR was an independent prognostic factor of RFS in colorectal cancer patients (hazard ratio: 7.757, 95% confidence interval: 1.462-41.152, p = 0.016)., Conclusion: Lower LMR was associated with poor prognosis in colorectal cancer patients; whereas, higher circulating MDSCs were observed in patients with lower LMR.

Severe malnutrition accompanied by sarcopenia and cachexia, is strongly associated with the surgical and oncological outcomes in cancer patients. The aim of the present study was to clarify the clinical significance of sarcopenia and its correlation with sarcopenia-associated miRNA in colorectal cancer (CRC). A total of 167 CRC patients were enrolled in the present study. We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC). The expression of miR-21 in CRC tissues and preoperative serum was evaluated using quantitative PCR. Despite the lack of significant correlation between IMAC and disease-correlated factors, decreased PMI was significantly associated with well-established clinicopathological factors for disease progression. Decreased PMI was an independent prognostic factor for both overall survival and disease-free survival and was an independent risk factor for various types of metastasis. In contrast to the expression of tissue miR-21, the expression of serum miR-21 was significantly increased in CRC patients with low PMI. Furthermore, postoperative PMI was drastically improved compared with preoperative PMI in CRC patients with potentially curative resections. In conclusion, skeletal muscle mass may be a prognostic and predictive biomarker for distant metastasis in CRC patients and quantification of serum miR-21 expression could help clinicians make decisions regarding nutrition intervention strategies in CRC patients.

Background: Preoperative hypoalbuminemia is a well-known risk factor for anastomotic leakage after colorectal surgery, but the association between perioperative albumin level and anastomotic leakage has not been fully investigated in curative colorectal cancer (CRC) patients., Methods: In total, 200 CRC patients (Stage I-III) undergoing curative laparoscopic surgery between January 2004 and December 2013 were enrolled in this study. We collected data on surgical factors, perioperative levels of serum albumin and inflammatory markers, and perioperative factors affecting hypoalbuminemia from 196 CRC patients to assess the relation to anastomotic leakage., Results: Anastomotic leakage occurred in 11 cases (5.6%) and the frequency was higher in rectal cancer patients (p = 0.0044). There was no significant difference of preoperative serum albumin level between the anastomotic leakage group (AL) and the nonanastomotic leakage group (NAL). Postoperative serum albumin levels in AL were significantly lower than in NAL [postoperative day (POD) 0, p = 0.0004; POD1, p = 0.0001; POD3, p = 0.0004; and POD7, p = 0.0021]. On multivariate analysis, lower average level of serum albumin on POD1 and POD3 {odds ratio (OR) [95% confidence interval (CI)] = 7.53 (1.60-55.80), p = 0.0095}, higher average level of serum white blood cells on POD1 and POD3 [OR (95% CI) = 7.24 (1.40-59.25), p = 0.0165], and surgery for rectal cancer [OR (95% CI) = 15.18 (3.26-93.99), p = 0.0004] were independent risk factors for anastomotic leakage., Conclusion: Lower early postoperative serum albumin levels are a potentially valuable indicator of anastomotic leakage in CRC patients undergoing curative surgery., (Copyright © 2016. Published by Elsevier Taiwan.)

Background: Although patients with metastatic colorectal cancer (CRC) are often unable to undergo treatment after resection of primary tumors, identifying such patients before surgery is not easy. In this study, we evaluated the association among clinicopathological findings, survival outcomes, and ability to undergo multimodal therapy after primary tumor resection in patients with Stage IV CRC., Methods: We collected clinicopathological findings and preoperative laboratory data, including carcinoembryonic antigen (CEA) and systemic inflammatory response markers for 92 patients who were treated for Stage IV CRC between 2005 and 2014. We used multivariate analysis on factors that affect prognosis and ability to undergo postoperative treatment., Results: Postoperative multimodal therapy improved overall survival (OS) significantly. Among serum markers, elevated CEA, neutrophil-to-lymphocyte ratio, and modified Glasgow prognosis score (mGPS) were significant indicators of shorter OS. In multivariate analysis, low performance status (P = 0.003), undifferentiated histology type (P = 0.019), and elevated mGPS (P = 0.042) were independent predictors of worse prognosis; and older age (P = 0.016), right-sided colon cancer (P = 0.043), and elevated mGPS (P = 0.031) were independent risk factors for difficulty of introducing postoperative multimodal therapy., Conclusions: Preoperative mGPS is a useful objective indicator for CRC patients with multiple metastases who are able to undergo primary site resection followed by postoperative multimodal therapy.

Introduction: The significance of the ectopic gastric phenotype remains unclear in patients with colorectal laterally spreading tumors (LSTs). We investigated clinicopathologic differences among LST subtypes, aiming to identify factors indicative of malignant transformation and invasion that are linked to ectopic gastric phenotype and tumor progression., Materials and Methods: We analyzed the morphologic characteristics of 105 colorectal LSTs resected by endoscopic submucosal dissection. LSTs were classified into 2 subtypes: granular (G-LST) and nongranular (NG-LST). Resected LSTs were analyzed histologically and were immunohistochemically stained for MUC5AC, MUC6, chromogranin A, CD10, and SOX2., Results: The 105 LSTs included 60 G-LSTs and 45 NG-LSTs. By histology, G-LSTs comprised 5 adenomas with low-grade dysplasia (LAs), 45 adenomas with high-grade dysplasia (HAs), and 10 adenocarcinomas invading the submucosa (SMs). NG-LSTs comprised 8 LAs, 25 HAs, and 12 SMs. MUC5AC positivity was significantly higher in G-LSTs compared to NG-LSTs (P = .002), and MUC5AC positivity in HA lesions was significantly higher than in LA lesions (P = .01). MUC6 and SOX2 positivity in SM G-LSTs, and chromogranin A positivity in SM NG-LSTs were significantly higher than in HAs (P = .01, .01, and .03, respectively). CD10 positivity in SM NG-LSTs was significantly higher than in HAs and LAs (P = .02 and .01, respectively)., Conclusion: Ectopic gastric and intestinal phenotypes, neuroendocrine cell differentiation, and SOX2 expression differ according to tumor grade in colorectal LSTs, and these markers are correlated with early tumor progression in each LST subtype., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Excess body weight is associated with a risk of several malignancies, including colon cancer. However, the oncological significance of evaluating body mass index (BMI) preoperatively in colorectal cancer (CRC) patients undergoing curative surgery has not been fully evaluated., Methods: Clinicopathological findings including BMI and laboratory data [carcinoembryonic antigen (CEA) and neutrophil/lymphocyte ratio (NLR)] from 358 curative CRC patients (open surgery group: n = 157; laparoscopic surgery group: n = 201) were assessed as indicators of survival outcome. BMI <20 was defined as underweight in both groups., Results: Not all categories of pathological findings were associated with BMI in both groups. Patients with BMI <20 showed significant poorer overall survival (OS) in the open surgery group. In addition, patients with BMI <20 in the laparoscopic surgery group were also significantly worse in OS and disease-free survival (DFS). Furthermore, multivariate analysis demonstrated that BMI was validated as independent predictors for OS and DFS in both groups. BMI had a significant negative correlation with NLR, which reflects host immune response in both groups., Conclusions: Lower BMI is a promising predictor of recurrence and prognosis in curative CRC patients.

Background: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab., Patients and Methods: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396., Results: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months., Conclusion: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC., Clinical Trials Number: UMIN000001396., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Acute malignant colorectal obstruction (AMCO) is an emergency associated with colorectal cancer (CRC). Emergency surgery is standard therapy for AMCO, and 1-stage surgery without colostomy is preferable, but it is occasionally difficult in the emergency setting. A self-expandable metallic stent (SEMS) enables noninvasive colonic decompression and subsequent 1-stage surgery, which has been widely applied for CRC with AMCO. However, recent accumulation of high-quality evidence has highlighted some problems and the limited efficacy of SEMS for AMCO. In palliative settings, SEMS placement reduces hospital stay and short-term complication rates, whereas it increases the frequency of long-term complications, such as delayed perforation. SEMS placement does not seem compatible with recent standard chemotherapy including bevacizumab. As a bridge to surgery, while SEMS placement provides a lower clinical success rate than emergency surgery, it can facilitate primary anastomosis without stoma. However, evidence regarding long-term survival outcomes with SEMS in both palliative and bridge to surgery settings is lacking. The efficacy of transanal colorectal tube placement, another endoscopic treatment, has been reported, but its clinical evidence level is low due to the limited number of studies. This review article comprehensively summarizes the current knowledge about surgical and endoscopic management of CRC with AMCO.

Aim: The aim of this study was to investigate the correlations between clinicopathological findings, laboratory data and survival outcome in patients undergoing curative laparoscopic surgery for colorectal cancer (CRC)., Patients and Methods: Clinicopathological findings and laboratory data, including tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) and systemic inflammatory response indicators, neutrophil-to-lymphocyte ratio (NLR) and modified Glasgow prognosis score (mGPS), for 204 patients (tumor stage I-III) undergoing laparoscopic curative surgery for CRC were collected., Results: Elevated CA19-9 and mGPS, and body mass index (BMI) <20 kg/m(2) were significant indicators of poorer overall survival, while CA19-9 and BMI were validated as independent predictors of overall survival. In addition, BMI <20 kg/m(2) was a significant independent factor predictive of poorer disease-free survival. BMI significantly negatively correlated with NLR, which reflects the patients' immune response., Conclusion: Lower BMI is a promising predictor of recurrence and poor prognosis in patients treated by laparoscopic surgery for CRC with curative intent., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Our recent prospective study found equivalent accuracy of magnifying chromoendoscopy (MC) and endoscopic ultrasonography (EUS) for diagnosing the invasion depth of colorectal cancer (CRC); however, whether these tools show diagnostic differences in categories such as tumor size and morphology remains unclear. Hence, we conducted detailed subset analysis of the prospective data., Methods: In this multicenter, prospective, comparative trial, a total of 70 patients with early, flat CRC were enrolled from February 2011 to December 2012, and the results of 66 lesions were finally analyzed. Patients were randomly allocated to primary MC followed by EUS or to primary EUS followed by MC. Diagnoses of invasion depth by each tool were divided into intramucosal to slight submucosal invasion (invasion depth <1000 μm) and deep submucosal invasion (invasion depth ≥1000 μm), and then compared with the final pathological diagnosis by an independent pathologist blinded to clinical data. To standardize diagnoses among examiners, this trial was started after achievement of a mean κ value of ≥0.6 which was calculated from the average of κ values between each pair of participating endoscopists., Results: Both MC and EUS showed similar diagnostic outcomes, with no significant differences in prediction of invasion depth in subset analyses according to tumor size, location, and morphology. Lesions that were consistently diagnosed as Tis/T1-SMS or ≥T1-SMD with both tools revealed accuracy of 76-78%. Accuracy was low in borderline lesions with irregular pit pattern in MC and distorted findings of the third layer in EUS (MC, 58.5%; EUS, 50.0%)., Conclusions: MC and EUS showed the same limited accuracy for predicting invasion depth in all categories of early CRC. Since the irregular pit pattern in MC, distorted findings to the third layer in EUS and inconsistent diagnosis between both tools were associated with low accuracy, further refinements or even novel methods are still needed for such lesions., Trial Registration: University hospital Medical Information Network Clinical Trials Registry UMIN 000005085.

Aim: We investigated whether serum markers and clinical factors could be used to preoperatively predict lymph node (LN) metastasis in colorectal cancer (CRC)., Patients and Methods: The present study enrolled 157 curative CRC patients for whom preoperative serum carcinoembryonic antigen (CEA), systemic inflammatory markers (C-reactive protein (CRP) and angiopoietin-like protein 2 (ANGPTL2)) and objective preoperative clinical factors were available as indicators of pathological LN status., Results: Specific clinical factors, including gender, tumor size, histopathology of biopsy sample and tumor morphology, were significantly correlated with LN metastases. Additionally, CEA, CRP and ANGPTL2 levels were also predictive factors for LN status. Multivariate analysis revealed that clinical factors, including gender, histopathology, tumor morphology and ANGPTL2, were identified as independent predictive factors for LN metastases. A combination of clinical factors reached high predictive accuracy of LN metastases and, combined with clinical factors, ANGPTL2 further improved the accuracy., Conclusion: Serum ANGPTL2 improves preoperative detection of LN metastasis in CRC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Angiopoietin-like protein 2 (ANGPTL2) is a mediator of chronic inflammation and inflammatory carcinogenesis. The biologic and clinical significance of ANGPTL2 remains unknown in human cancer. Therefore, we investigated the function of ANGPTL2 and evaluated its clinical significance in both primary tumors and matched sera in patients with colorectal cancer., Experimental Design: A colorectal cancer cell line was transfected with siRNA against ANGPTL2 for the assessment of its function. We examined ANGPTL2 expression in colorectal cancer tissues (n = 195) by immunohistochemistry. Finally, we screened serum ANGPTL2 levels from 32 colorectal cancers and 23 normal controls (NC), and validated these results in serum samples obtained from 195 colorectal cancers and 45 NCs by ELISA., Results: Knockdown of ANGPTL2 in vitro significantly inhibited cell proliferation, migration, and invasion, whereas it enhanced anoikis. ANGPTL2 was overexpressed in colorectal cancer tissues, and was significantly associated with advanced T stage, lymph node, and liver metastasis. Likewise, serum ANGPTL2 levels in colorectal cancers were significantly higher than NCs (P < 0.01), and allowed distinguishing of colorectal cancers from NCs with high accuracy (AUC = 0.837). The subsequent validation step confirmed that serum ANGPTL2 levels in colorectal cancers were significantly higher than in NCs (P < 0.0001), and had a high AUC value (0.885) for distinguishing colorectal cancers from NCs. High serum ANGPTL2 was significantly associated with advanced T stage, lymph node and liver metastasis, early relapse, and poor prognosis in colorectal cancers., Conclusion: Serum ANGPTL2 is a novel diagnostic and recurrence-predictive biomarker in patients with colorectal cancer., (©2014 American Association for Cancer Research.)

Background & Aims: Magnifying chromoendoscopy (MC) and endoscopic ultrasonography (EUS) are used to estimate the depth of colorectal cancer (CRC) invasion, but it is not clear which procedure is more accurate. We performed a prospective study to compare MC and EUS., Methods: A total of 70 patients with an early stage flat CRC lesion were enrolled at 6 institutions in Japan and randomly assigned to groups assessed by MC followed by EUS or EUS followed by MC. Results from MC and EUS measurements of 66 lesions were included in the final analysis. The invasion depth of each lesion was measured by each procedure and categorized as mucosal to slight submucosal (depth <1000 μm) or deep submucosal (depth ≥ 1000 μm); measurements were compared with the final diagnosis on the basis of the pathology analysis. All participating examiners achieved a mean κ value ≥ 0.6 for both MC and EUS before this trial., Results: MC and EUS each measured the depth of lesion invasion with 71.2% accuracy (correctly for 47 of 66 lesions). MC identified lesions with deep submucosal invasion with 74.2% sensitivity and 68.6% specificity, whereas EUS identified them with 67.7% sensitivity and 74.3% specificity. The differences between MC and EUS measurements did not differ significantly. However, MC required significantly shorter observation time than EUS (361.7 ± 164.5 seconds vs 451.2 ± 209.4 seconds, P = .002)., Conclusions: MC and EUS are equally accurate in estimating the invasion depth of early stage CRC lesions. However, neither procedure has sufficient diagnostic accuracy to be used as the standard. University Hospital Medical Network Clinical Trials Registry, Number: UMIN 000005085., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Cancer research is currently focused on blocking the metastatic process at its early steps. Some particularly attractive targets are metastasis suppressor genes, which control cancer cell dissemination. The aim of this study was to clarify the relationship between the expression of KiSS1, a metastasis suppressor gene, and disease progression in colorectal cancer patients. One-hundred and seventy-five patients who underwent surgery for colorectal cancer were enrolled in this study. We analyzed KiSS1 mRNA expression by real-time reverse transcription PCR in colorectal cancer tissue and paired adjacent normal mucosa. KiSS1 protein expression in early- and advanced-stage colorectal cancer samples was determined by immunohistochemical analysis. Decreased KiSS1 expression was significantly associated with lymph node metastasis and was an independent prognostic factor. Logistic regression analysis revealed that decreased KiSS1 expression was an independent risk factor for lymph node metastasis. Immunohistochemical analysis indicated that KiSS1 was highly expressed in the cell cytoplasm of early-stage colorectal cancer cells. The loss of KiSS1 appears to correlate with the progression of lymph node metastasis. An assessment of KiSS1 expression may assist in the accurate colorectal cancer diagnosis and may contribute to predict clinical outcomes.

Purpose: Although KRAS mutation has been identified as a negative predictive biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR antibodies work by blocking ligand binding, but the significance of EGFR ligands in mCRC has not been completely described. This study was conducted to identify the correlation between all seven EGFR ligands and clinical outcomes in mCRC treated with anti-EGFR antibodies. Furthermore, we determined an appropriate predictive strategy for anti-EGFR antibodies using these EGFR ligands., Methods: Among 36 mCRC patients who had been treated with cetuximab or panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated properly as the second and further lines and analyzed the relationship between immunoreactivity to seven EGFR ligands and clinical outcomes., Results: Good clinical outcomes were associated with immunoreactivity against amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor-α (TGF-α), and epiregulin (EREG). Further, patients with immunoreactivity to greater than two of these four ligands (AR, HB-EGF, TGF-α, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p = 0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when compared with patients with immunoreactivity against zero or one ligand., Conclusions: Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF, TGF-α, and EREG) might be a novel predictive biomarker and may help optimize patient selection for cetuximab and panitumumab therapy in patients with mCRC.

Background and Study Aims: Acute colorectal obstruction (ACO) often accompanies colorectal cancer (CRC) and requires urgent treatment, but achieving elective laparoscopy-assisted colectomy (LAC) is difficult in this setting. The aim of the current study was to assess the clinical outcomes of a transanal tube (Dennis colorectal tube [DCT]) for CRC with ACO, focusing in particular on the impact of the DCT on subsequent elective LAC., Patients and Methods: Among 1142 patients who underwent surgery for CRC between January 2007 and December 2011, 92 patients with ACO were identified retrospectively. Of these 92 patients, the DCT procedure was performed in 66 patients who fulfilled the indications for DCT, and these patients were included in the study., Results: All 66 patients presented with complete obstruction. Technical and clinical success rates for DCT were 93.9 % and 86.4 %, respectively. Perforation after DCT occurred in 4.5 % and the mortality rate was 1.5 %. The rate of LAC was 48.5 %, and the rate of primary stoma was 13.6 %. For curative stage II/III CRC with ACO, DCT resulted in a primary stoma rate of 13.6 %, a one-stage surgery rate of 90.9 %, a LAC rate of 50.0 %, and a 3-year survival rate of 73.1 %. For stage II/III CRC cases with clinical success by DCT, the one-stage surgery rate was 97.4 % and the LAC rate was 56.4 %., Conclusions: DCT achieved a high rate of clinical success and enabled safe one-stage surgery and LAC for CRC with ACO. DCT followed by LAC is proposed as a promising non-invasive strategy for CRC with ACO., (© Georg Thieme Verlag KG Stuttgart · New York.)

Dual-specificity protein phosphatase 4 (DUSP4), a negative regulator of extracellular-regulated kinase activity, is a potential mediator of resistance to chemotherapy and a tumor suppressor. The aim of this study is to clarify the association between DUSP4 gene expression and clinical outcome in patients with colorectal cancer. Patients who underwent surgery for colorectal cancer were enrolled in this study (n = 212). We investigated DUSP4 gene expression by real-time reverse transcription polymerase chain reaction in colorectal cancer tissue and paired normal mucosa. Immunohistochemical analyses of DUSP4 and ERK1/2 were also conducted. Additionally, we examined the relationship between gene expression and KRAS mutation in 74 of the 212 patients. DUSP4 expression in tumor tissues was significantly higher than that in matched normal mucosa (P < 0.0001). Decreased DUSP4 expression was significantly associated with advanced T classification, lymphatic invasion, vascular invasion, advanced stage, and liver and lung metastases. Logistic regression analysis revealed that decreased DUSP4 expression was an independent risk factor for synchronous distant metastases (P = 0.006). Increased DUSP4 expression was significantly associated with better prognosis (P = 0.0162). Immunohistochemical examination showed DUSP4 expression in the nucleus and cytoplasm of cancer cells, and no correlation was observed between DUSP4 and ERK1/2 expression. There was no significant correlation between DUSP4 expression and KRAS mutation. In conclusion, DUSP4 expression in colorectal cancer was negatively correlated with factors reflecting tumor progression, including distant metastases. Our data suggest that DUSP4 may act as a tumor suppressor in colorectal cancer.

Background: Chemotherapy-induced interstitial lung disease (ILD) in colorectal cancer (CRC) patients is rarely reported, but its clinical features remain to be clarified., Patients and Methods: Using a computerized database, we retrospectively identified patients who developed ILD from 734 patients with CRC treated with infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) or infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) from April 2005 to December 2008 at the National Cancer Center Hospital East., Results: Of 734 patients, 11 patients developed ILD (1.5%) and 4 of those patients died (0.54%). Of the 11 patients, 10 showed pulmonary shadows other than lung metastases before chemotherapy. ILD developed during FOLFOX in six patients, at 137 days after completion of FOLFOX in one patient, during oxaliplatin interruption of FOLFOX in one patient and during FOLFIRI in the remaining three patients. FOLFOX had been administered at some point for all ILD patients, with a median of 10 cycles (range 2-17 cycles) and a median dose of administered oxaliplatin of 850 mg/m(2) (range 170-1445 mg/m(2))., Conclusions: ILD following FOLFOX or FOLFIRI is an uncommon but life-threatening complication. Care must be taken regarding the onset of ILD, not only during but also after chemotherapy for CRC.

Unlabelled: Beta-catenin is a component of the Wingless/Wnt signaling pathway and can activate target genes associated with proliferation and invasion, linking with the APC gene. The purpose of this study was to investigate whether nuclear expression of beta-catenin in cells at the invasive front or in the vessels was associated with liver metastasis in human colon cancer., Patients and Methods: One hundred and eighteen patients with colorectal carcinoma who underwent surgical resection (45 patients with liver metastasis and 73 patients without liver metastasis at least 5 years after surgery) were included in the study. Proliferative activity was determined in several areas (tumor center, invasive front and in the vessels) by immunohistochemistry and whether it was correlated with liver metastasis was examined., Results: In 73.1% of primary tumors, positive staining for beta-catenin was detected in the membranes at the tumor center and in the nuclei at the invasive front. In 32 patients (26.9% of all cases), beta-catenin was expressed exclusively in the nuclei of the carcinoma cells throughout the tumors. Significant differences in expression of nuclear beta-catenin in the primary tumors were detected between the liver metastasis and non-liver metastasis groups at the tumor center (p=0.004), invasive front (p=0.021) and in the vessels (p<0.0001)., Conclusion: Nuclear accumulation of beta-catenin in cellular cells at the invasive front and in the vessels was the most powerful predictor of liver metastasis in colorectal cancer. This may be an important marker in the selection of patients for adjuvant therapy or other treatment modalities.

Background: Galectin-3, a beta-galactoside-binding protein, has been associated with various biological processes, such as cell adhesion, recognition, proliferation, differentiation and apoptosis. The aim of this study was to determine the relationship of galectin-3 expression to clinicopathological findings in patients with colorectal cancer. Furthermore, the correlation between the expression of galectin-3 and beta-catenin, and the Ki-67 labeling index were investigated., Materials and Methods: Immunohistochemical assessment of galectin-3, beta-catenin and Ki-67 expression was performed on samples from 108 patients with colorectal cancer. The expression of galectin-3 was classified at the tumor surface and the invasive front, and its relationship with clinicopathological factors was considered from a statistical viewpoint., Results: There was significant liver metastasis when the expression of galectin-3 was lower at the invasive front of a tumor compared to its surface (p = 0.04). There were also significant correlations between beta-catenin expression at the tumor surface and liver metastasis and tumor stage (p = 0.03, p = 0.04 respectively)., Conclusion: The reduction of galectin-3 expression is associated with the invasion and metastasis of colorectal cancer. A possible involvement of galectin-3 expression in tumor invasion, metastasis and proliferation in patients with colorectal cancer is suggested.

Recently, overexpression of EphA2, a member of the Eph family of receptor tyrosine kinases, has been reported in several cancers. Reduced expression of E-cadherin, an intercellular adhesion molecule of epithelial cells, has been reported to be associated with aggressive clinicopathological phenotypes in various cancers. In epithelial cells, EphA2 and E-cadherin co-localize to sites of cell-cell contact, and it has been shown that E-cadherin regulates EphA2. This study aimed to clarify the relationship between the expression of the EphA2 and E-cadherin proteins and clinicopathological characteristics, with reference to the expression levels of both EphA2 and E-cadherin, in patients with colorectal cancer. We performed immunohistochemical staining of EphA2 and E-cadherin with EphA2 and E-cadherin monoclonal antibodies in samples from 194 primary lesions of colorectal cancer. The expression level of EphA2 had a statistically significant relationship with liver metastasis, lymphatic vessel invasion and clinical stage (p=0.0477, 0.0316 and 0.0467, respectively). In addition, the positivity rate of EphA2 was significantly higher in primary lesions with lymph node metastasis than in those without metastasis (p=0.0014). However, the expression level of E-cadherin had an inverse relationship with both differentiation level of the tumor and lymphatic vessel invasion (p=0.0430 and 0.0320, respectively). Furthermore, a significant relationship between the expression of EphA2 and E-cadherin was observed. In conclusion, our study revealed that the overexpression of EphA2 protein in colorectal carcinoma tissue correlates closely with cancer progression and hematogenous and lymphogenous metastasis, suggesting that both EphA2 and E-cadherin may play an important role in tumor metastasis in colorectal cancer.

Purpose: Recent advances have made possible the treatment of small invasive colorectal cancer by means of polypectomy or endoscopic mucosal resection. CD44 expression in cancer cells was identified as an indicator of lymph-node metastasis, which could be evaluated in specimens removed by colonoscopy., Methods: The correlation between lymph-node metastasis and the expression of standard-type CD44 in cancer cells was examined immunohistologically using the invaded cancer cells of 61 tissue samples of superficially invasive colorectal cancer. We defined the above as invasive cancer restricted within the colorectal wall. Of the 61 samples, 31 had submucosal invasion and 30 had muscular invasion., Results: Standard-type CD44 expression in the area of invasion in cases with lymph-node metastasis was remarkably down-regulated. In 43 cases with no lymph-node metastasis, 36 (83.7 percent) of patients had CD44 expression in invaded cells, whereas only two of 18 cases (11.1 percent) with lymph-node metastasis had expression of standard-type CD44 in the same area (P < 0.0001). A total of 69.6 percent (16/23) of patients with loss of standard-type CD44 expression in invaded sites were found to have positive metastasis in the lymph nodes. These results suggest that standard-type CD44 in invasive colon cancer cells could suppress metastasis to the regional lymph nodes., Conclusion: In cases of invasive colorectal cancer, the loss of standard-type CD44 expression in the invaded area is a sensitive marker for metastasis to the lymph nodes. Further investigation with larger patient groups is required to clarify the reliability of loss of standard-type CD44 expression as an indicator for additional surgery after endoscopic resection of submucosal invasive colorectal carcinoma.

Several lines of evidences from us or other authors had shown that tumor cells revert their phenotypes and differentiate by the elimination of oncogenes amplified on the acentric double minutes (DMs). The selective incorporation of DMs into the cytoplasmic micronuclei was thought to be involved in this elimination, however, the mechanism by which the content of micronuclei was eliminated from the cells remains to be discovered. In this report, we show the finding and the characterization of the extruded micronuclei in the culture fluid of human COLO 320DM tumor line, and suggest that the extrusion of micronuclei mediates the selective elimination of DMs. The extracellular micronuclei enriched with DMs had an apparently normal cytoplasmic membrane, decondensed chromatin and nuclear lamin protein, and their DNA did not suffer any extensive degradation. These characteristics were closely related to their cytoplasmic counterpart and clearly differentiated from the apoptotic bodies. We also developed a method for purifying the extracellular micronuclei. In this paper, the implications of the micronuclear extrusion are discussed.